DISSOCIATION OF THE DECARBOXYLASE-INHIBITING AND NOREPINEPHRINE-DEPLETING EFFECTS OF -METHYL-DOPA, -ETHYL-DOPA, 4-BROMO-3-HYDROXY-BENZYLOXYAMINE AND RELATED SUBSTANCES

¹ Experimental Therapeutics Branch, National Heart Institute, Bethesda, Maryland

The decarboxylase-inhibiting effects of several drugs were studied in vitro. -Methyl-dopa was slightly more potent than -ethyl-dopa but less potent than NSD-1034, NSD-1039 or NSD- 1055 as a decarboxylase inhibitor. The decarboxylation of -ethyl-dopa to -ethyl-dopamine was not detected in a system which formed easily measurable quantities of -methyl-dopamine from -methyl-dopa. The decarboxylation of -methyl-dopa was completely inhibited by low concentrations of NSD-1034, NSD-1039 or NSD-1055.

The same drugs were examined for in vivo effects on decarboxylase activity and norepinephrine levels in the brain and heart of the guinea pig. Inhibition of decarboxylase by -methyl-dopa and by -ethyl-dopa required large doses and was of short duration. NSD- 1039 and NSD-1055 were much more potent decarboxylase inhibitors; their effects diminished only slightly in 24 hours. Neither NSD- 1055 nor -ethyl-dopa depleted norepinephrine from tissue. Norepinephrine depletion by - methyl-dopa was prevented by pretreatment with suitable doses of NSD-1055. -Ethyl-dopamine was found to be effective in depleting norepinephrine levels in the heart.

These findings support the belief that decarboxylase inhibition does not decrease tissue norepinephrine levels and that -substituted amino acids are dependent upon decarboxylation to the corresponding amines for their pharmacologic and norepinephrine-depleting effects.